Sulfonyl or sulfinyl substituted indenyl alcohols

ABSTRACT

NEW SUBSTITUTED INDENYL ALCOHOLS AND DERIVATIVES THEREOF WHICH HAVE ANTI-INFLAMMATORY, ANTI-PYRETIC AND ANALGESIC ACTIVITY. ALSO INCLUDED ARE METHODS OF PREPARING SAID INDENYL COMPOUNDS, PHARMACEUTICAL COMPOSITIONS HAVING SAID INDENYL COMPOUNDS AS AN ACTIVE INGREDIENT AND METHODS OF TREATING INFLAMMATION.

United States Patent a 3,819,716 Patented June 25, 1974 ABSTRACT OF THEDISCLOSURE New substituted indenyl alcohols and derivatives thereofwhich have anti-inflammatory, anti-pyretic and analgesic activity. Alsoincluded are methods of preparing said indenyl compounds, pharmaceuticalcompositions having said indenyl compounds as an active ingredient andmethods of treating inflammation.

SUMMARY OF THE INVENTION This invention relates to new substituted 1-alkyl. idene (or heteroalkylidene) indenyl alcohols, ethers and reverseesters and to processes for producing the same. This invention alsorelates to pharmaceutical compositions containing said indenyl alcoholcompounds as an active ingredient and to methods of treating pain, feveror inflammation by administering these particular compositions topatients.

DESCRIPTION AND PREFERRED EMODIMENTS The invention is more particularlydirectly to new substituted indenyl alcohol compounds having thefollowing general formula:

wherein R and R each may be hydrogen, halogen, alkyl, alkenyl, aryl,haloalkyl, alkylthio, arylthio, aralkylthio, amino, alkylarnino,dialkylamino, acylarnino, N-heterocyclic, hydroxy, alkoxy, alkenyloxy,alkynyloxy, aralkoxy,

haloalkoxy, carboXY, alkoxycarbonyl, alkoxycarbonyl or vR and R togethermay be alkylene or keto;

R may be hydrogen, alkyl, haloalkyl, alkenyl, alkynyl or trihalomethyl;

R R R Rq, R and R each may be hydrogen, alkyl, acyloxy, aryloxy, alkoxy,nitro, amino, acylamino, alkylamino, dialkylamino, alkenyl, alkynyl,alkenyloxy, dialkylaminoalkyl, sulfamyl, alkylthio, alkylsulfinyl,alkylsulfonyl, hydroxy, hydroxyalkyl, acyl, halo, cyano, carboxyl,carboalkoxy, carbamido, haloalkyl, cycloalkyl, trifluoromethyl orcycloalkyloxy;

X may be alkylene, alkenylene, alkynylene, O, S, carbonyl, sulfinyl orNR wherein R is hydrogen or alkyl;

@ may be aryl or heteroaryl;

M may be hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,

alkanoyl, haloalkanoyl, alkenoyl, alkynoyl, cycloalkanoyl or arylcontaining less than three fused rings or Y wherein Y is:

This

R Ho

The aryl or heteroaryl substituent, 9 may include an aryl ring systemsuch as benzene, naphthalene, biphenyl or a heteroaryl ring system suchas a pyrrole, furan, thiophene, pyridine, imidazole, pyrazine, thiazole,pyrimidine, benzothiazole, pyrazole, oxazole, pyrane, pyridazine,indole, thionaphthene, benzofuran, benzimidazole, azaindole,benzoxyrane, quinoline, isoquinoline, quinoxaline, naphthyridine orbenzoxazole and may be substituted with any of the aforementioned R andR substituents.

In the preferred compounds of this invention R and R are hydrogen, Cloweralkyl, C loweralkenyl, phenyl or benzyl; R is hydrogen, Cloweralkyl or C ehloro, bromo or fluoro loweralkyl; R R R and R may behydrogen, halo (chloro, bromo, fluoro), C loweralkyl, halo C loweralkyl,C loweralkoxy, cyano, nitro, amino, C loweralkylamino, Cdiloweralkylamino, C loweralkanoylarnino, C loweralkanoyloxy, hydroxy, Cloweralkanoyl, C loweralkanoyl, C loweralkenyloxy or trifiuoromethyl; Rand R are each hydrogen, chloro, bromo, fluoro, C loweralkylthio, Cloweralkyl, trifiuoromethyl, C loweralkylsulfonyl, C loweralkylsulfinyl,C diloweralkylsulfamyl, nitro or C loweralkoxy; X is C, alkylene, Calkenylene, C alkynylene or -O-;

n is l or 2;

pyridine, thiophene, pyrazine, pyrrole, furan, pyrimidine,benzothiazole, thiazole, pyrazole, oxazole, pyrane, pyridazine, indole,thionaphthene, benzofuran, benzimidazole, azaindole, quinoline,isoquinoline, quinoxaline, naphthyridine or benzoxazole; and M ishydrogen, C loweralkyl, phenyl or benzyl.

In the most preferred aspect of this invention R and R is hydrogen, Cloweralkyl, phenyl or benzyl; R is hydrogen or C loWeralkyl; R R R and Rare each hydrogen, chloro, bromo, fiuoro, C loweralkyl, C loweralkoxy,nitro, amino, C loweralkylamino, halo C loweralkyl, C diloweralkylamino,C loweralkanoyloxy, hydroxy C loweralkanoylox'y or trifluoromethyl, atmost only 2 of R R R or R being other than hydrogen at any one time; Rand R are each hydrogen, C loweralkyl, C loweralkoxy, Cloweralkylsulfinyl, C loweralkylsulfonyl, chloro, bromo, fluoro, Cloweralkylthio, trifluoromethyl, C loweralkylsulfamyl, Cdiloweralkylsulfamyl or nitro; X is C alkylene, C alkenylene, Calkynylene or O--; n is 1 or 2; is phenyl; and M is hydrogen; C;loweralkyl, benzyl or phenyl.

This invention also relates to a method of treating pain, fever orinflammation in patients using a compound of Formula I, particularly andespecially the preferred compounds as the active constituent.

is the residue of benzene, naphthalene,

The compounds of the instant invention can be used to treat inflammationby reducing inflammation and relieving pain in such diseases asrheumatoid arthritis, osteoarthritis, gout, infectious arthritis andrheumatic fever. The compounds of Formula I can also be used as ananti-pyretic and would be administered and used in the same manner andin the same dosage ranges as if they were being used to treatinflammation as discussed further on.

The treatment of inflammation in accordance with the method of thepresent invention is accomplished by topically, orally, rectally orparenterally administering to patients a composition of a compound ofFormula I, particularly the especially preferred compounds in a nontoxicpharmaceutically acceptable carrier.

The non-toxic pharmaceutical carrier may be, for example, either a solidor a liquid. Exemplary of solid carriers are lactose, corn starch,gelatin, talc, sterotix, stearic acid, magnesium stearate, terra alba,sucrose, agar, pectin, Cab-O-Sil and acacia. Exemplary of liquidcarriers are peanut oil, olive oil, seasame oil and water. Similarly,the carrier or diluent may include a time delay material such asglyceryl monostearate or glyceryl distearate alone or with a wax.

Several pharmaceutical forms of the therapeutically useful compositionscan be used. For example, if a solid carrier is used, the compositionsmay take the form of tablets, capsules, powders, troches or lozenges,prepared by standard pharmaceutical techniques. If a liquid carrier isused, the preparation may be in the form of a soft gelatin capsule, asyrup, an aqueous solution or a liquid suspension. Suppositories may beprepared in a conventional manner by mixing the compounds of thisinvention with a suitable non-irritating excipient which is solid atroom temperature, but liquid at the rectal temperature. Such materialsare cocoa butter and polyethylene glycol. Gels and lotions for topicalapplication may be prepared in conventional manners.

The compounds of Formula I and of the compositions of this invention areto be administered in an amount suflicient to treat inflammation, thatis to reduce inflammation. Advantageously, the compositions will containthe active ingredient; namely, the compounds of Formula I in an amountof from about 0.1 mg. to 50 mg. per kg. body weight per day (5 mg. to3.5 g. per patient per day), preferably from about 1 mg. to mg./kg. bodyweight per day (50 mg. to 1 g. per patient per day).

The method of treatment of this invention comprises administering to apatient (animal or human), a compound of Formula I, particularly anespecially preferred compound admixed with a non-toxic pharmaceuticalcarrier such as exemplified above. The compounds of Formula I andparticularly the especially preferred compounds will be administered inan amount of from 0.1 mg. to 50 mg./kg. body weight per day, preferablyfrom about 1 mg. to about 15 mg. per kilogram body weight per day. Themost rapid and effective anti-inflammatory effect is obtained from oraladministration of a daily dsoage of from about 1 to 15 mg./kg./day. Itshould be understood, however, that although preferred dosage ranges aregiven, the dose level for any particular patient depends upon theactivity of the specific compound employed. Also many other factors thatmodify the actions of drugs will be taken into account by those skilledin the art in the therapeutic use of medicinal agents, particularlythose of Formula I, for example, age, body weight, sex, diet, time ofadminstration, route of administration, rate of excretion, drugcombination, reaction sensitivities and severity of the particulardisease.

The compounds of this invention may be prepared from their correspondingacids or esters. For example, a l-unsubstituted 3-indenyl acetic acid orester may be first converted to its corresponding alcohol by methodswell known in the art for reduction of an acid group or ester to analcohol group (such as with complex hydrides, for example, lithiumaluminum hydride or calcium borohydride, in such solvents astetrahydrofuran ether and the like), followed by condensation anddehydration with the appropriate aldehyde in the 1-position of theindene. This later reaction may readily be carried out by using a strongbase such as alkali hydroxide or alkoxide and the like, as the catalyst,the reaction can be carried out in a solvent, if desired andconveniently at temperatures of from 60 C. to the reflux tempertaure ofthe system. Alternatively, the l-substituted 3-indenyl acetic acid orester may be first prepared followed by reduction of the acid side chainto the alcohol. The ethers and reverse esters of these alcohols may beprepared by well known etherification or esterification reactions. Inthose cases wherein X is oxygen, it is preferred to convert thel-unsubstituted indene ester to the correspoding l-hydroxymethylcompound by reactions with ethyl formate and an alkali hydride, followedby reaction with an aryl halide to form the l-aryloxymethylidenecompound, and finally reduction of this compound to the correspondingB-ethanol compound.

The starting material, i.e., 1-unsubstituted-3-indenyl acetic acids oresters are known compounds as indicated by such as US. patents as US.3,654,349, 3,312,730 and others. The l-substituted derivatives thereofmay be readily prepared by condensation and dehydration of thel-unsubstituted-3-indenyl acetic acids or esters.

The following examples are given by way of illustration.

EXAMPLE 1 Ethyl-2-methy1-5-fluoro-3-indenylacetate A mixture of 0.1 moleof 2-methyl-5-fiuoro-3-indenyl acetic acid, 0.2 gm. of p-toluenesulfonic acid, in ml. of absolute ethanol and 75 ml. of dry benzene isrefluxed on a steam bath while distilling the solvent. After 17 hours,the residual solvent is removed under reduced pressure. The residue isslurried in aqueous soduim bicarbonate and then With water untilneutral. The resulting ethyl ester is then recrystallized from ethylacetate.

Similarly, when a-(2-methyl-5-methoxy-3-indenyl)propionic acid,2-methyl-7-fluoro-3-indenyl acetic acid, 2-methyl-6-fiuoro-3-indenylacetic acid, Z-methyl-S-trifluoromethyl-3-indenyl acetic acid,2-methyl-5-methoxy-3-indenyl acetic acid, 2-methyl-5-nitro-3-indenylacetic acid, 2-methyl-5,6-difluoro-'3-indenyl acetic acid,2-methyl-5-chloro-3-indenyl acetic acid,Z-methyl-S-dimthylamino-B-indenyl acetic acid,2-methy1-5-allyloxy-3-indenyl acetic acid, 2-methyl-5-cyano-3-indenylacetic acid, or Z-methyl-S-methoxy 6-fluoro-3-indenyl acetic acid,

is used in an equivalent amount in place of 2-methyl-5- fluoro-3-indenylacetic acid, there is obtained the corresponding ethyl acetate.

EXAMPLE 2 (A) 5-Fluoro-2-methyl-3-indenyl-}8-ethanol To a suspension oflithium aluminum hydride (1.0 g., 0.264 mole) in ether (50 ml.) is addedmethyl-S-fluoro- 2-methyl-3-indenylacetate (9.8 g., 0.0446 mole) inether (75 ml.) over 30 minutes. The mixture is heated at reflux for 3hours, cooled to 05 and methanol (50 ml.) added. Water (50 ml.) is addedslowly. Magnesium sulfate (10 g.) is added and the mixture is filteredthrough diatomaceous earth. The filtrate is dried (MgSO and concentratedto an oil. The oil is taken up in benzene and chromatographed on silicagel. After elution of some starting material and a mixed fraction,5-fluoro-2-methyl- 3-indenyl-fi-ethanol is obtained.

Similarly, when any of the other ethylacetate compounds obtained fromExample 1 are used in an equivalent amount in place of ethyl2-methyl-S-fluoro-B-indenyl acetate, in the above example, thecorresponding 13- ethanol compounds are obtaned.

(B) cisand trans-S-Fluoro-Z-methyl-1-(4'-methylsulfinylcinnamylidenyl -3-indenyl-,B-ethanol To a solution of5fluoro-'2-methyl-3-indenyl-B-ethanol from Example 1(A) (3.84 g., 0.020mole) in methanol (60 ml.) is added sodium methoxide (2.16 g., 0.04mole) and after solution p methylsulfinylcinnamaldehyde (0.02 mole). Themixture is heated at reflux for 5 hours, cooled, poured intoether-water, extracted with ether, dried (MgSOg), and concentrated to anoil in vacuo. The oil is taken up in methylene chloride andchromatographed on silica gel and eluted with ethyl acetate. Thefractions of eluate are concentrated to yield cisand trans 5fiuoro-Z-methyl-l-(4-methylsulfinylcinnamylidenyl) -'3-indenyl-fl-ethanol.

Similarly, when an equivalent amount of any of the other ethanolcompounds obtained from Example 2(A) above are used in place ofS-fluoro-Z-methyl-3-indenyl-;3- ethanol, there is obtained thecorresponding 1-(4 -methylsulfinylcinnamylidenyl) 3 indenyl-p-ethanolcompound.

Similarly, when an equivalent amount of the aldehyde of Table I below isused in place of 4-methyl-sulfinylcinnamaldehyde in the above procedure,the corresponding 1-substituted-Z-methyL5-fluoro-3-indenyl B ethanol isobtained.

TABLE I a-tolualdehyde cinnamaldehyde hydrocinnamaldehyde2-methoxycinnamaldehyde 4-methoxycinnamaldehyde 4-ethoxycinnamaldehyde3,4-dimethoxycinnamaldehyde 4-methylcinnamaldehyde4-t-butylcinnamaldehyde 2-nitrocinnamaldehyde 3-nitrocinnamaldehyde4-nitrocinnamaldehyde 4-dimethylaminocinnamaldehyde4-diethylaminocinnanamaldehyde 2-chlorocinnamaldehyde4-chlorocinnamaldehyde 2,4-dichlorocinnamaldehyde 4-bromocinnamaldehyde4-methylthi0cinnanamaldehyde 2-methylsulfinylcinnamaldehyde4-methylsulfonylcinnamaldehyde 4-chlor0-a-methylcinnamaldehyde4-chloro-2-nitrocinnamaldehyde 4-chloro-3-nitrocinnamaldehydeS-chloro-2-methylcinnamaldehyde 4-nitro-u-methylcinnamaldehyde4-nitro-B-methylcinnamaldehyde 4-nitro-B-phenylcinnamaldehydea-methylcinnamaldehyde u-ethylcinnamaldehyde B-methylcinnamaldehydeB-ethylcinnamaldehyde u-fi-dimethylcinnamaldehydeot-pentylcinnamaldehyde a-cyclopentylcinnamaldehyde3,4-methylenedioxycinnamaldehyde 3,4,5 -trimethoxycinnamaldehyde3,4-dimethoxy-a-methylcinnamaldehyde 4-isopropyl-a-methylcinnamaldehyde4-methoxyhydrocinnamaldehyde 2-methylhydrocinnamaldehyde4-methylhydrocinnamaldehyde 4-sec butylhydrocinnamaldehyde4-nitrohydrocinnamaldehyde 4-chlorohydrocinnamaldehyde 64-methylthiohydrocinnamaldehyde 4-methylsulfinylhydrocinnamaldehyde4-methylsulfonylhydrocinnam aldehyde 4-nitro-a-methylhydrocinnamaldehyde4-nitro-fl-methy1hydroeinn am aldehyde4-chloro-a-methylhydrocinnamaldehyde4-chloro-fl-methylhydrocinnamaldehyde a-methylhydrocinnamaldehyde,fi'methylhydrocinnamaldehyde a, a-dimethylhydro cinnamaldehyde4-chloro-a-tolu aldehyde 4-methoxy-a-tolualdehyde 4-methylthio-a-tolualdehyde a-methyl-a-tolualdehyde a-ethyl-a-tolu aldehyde4-nitro-a-methyl-a-tolualdehyde 4-chloro-wmethyl-a-tolualdehyde4-pheny1butan a1 4-phenyl-2-butenal 2-thienylacetaldehyde ,8- (2-thienylpropenal fl- 2-thienyl) propanal 3 -pyridylacetaldehyde4-pyridylacetaldehyde 2'-pyridylacetaldehyde 2'-furylacetaldehyde 5'-chloro-2'-thienylacetaldehyde u-naphthylacetaldehydefi-naphthylacetaldehyde fl- 2'-furyl prop enal 2-pyridyl propenal [3-a'-naphthyl) propen al [3- (3 -pyridy1) prop enal13-(4'-pyridyl)propenal p-(2'-fury1) ro ana1 3- (2-pyridyl) prop anal B-(a-naphthyl prop anal [3- 2-quino1yl) propanal fi- 2-pyrrolidinyl)propanal ,3- (2-benzofuranyl) propanal fl- 2'-quinolyl propenal fl-2'-pyrrolyidinyl propenal fl- 2'-naphthyl propenal B, 8-diphenylpropenal2-indanacetaldehyde 2-benzothiazole propenal 13- (3 -nitro-2'-thienyl)propen al 13- l-methyl-2-pyrrolyl propenal fl-( 1'-methyl-2'-pyridyl)propenal EXAMPLE 3cis-S-Fl-uoro-3-(Z-methoxyethyl)-2-methyl-l-(p-methylsulfinylcinnamylidenyl)-indeneTocis-S-fluoro-Z-methyl-l-(p-methylsulfinylcinnamylidenyl)-3-indenyl-B-ethano1from Example 2(B) (0.0017 mole) in dimethoxyethane (10 ml.) is addedoil-free sodium hydride (0.048 g., 0.002 mole) and the mixture isstirred at 25 for 1 hour. To the mixture is added methyl iodide (2.28g., 0.016 mole) and stirring at 25 is continued for 18 hours. Themixture is poured into methylene chloride-water, extracted withmethylene chloride, the methylene chloride extract washed with water,dried and concentrated. The concentrate is chromatographed over silicagel and the eluate concentrated to yield cis-5-fluoro-3-(Z-methoxyethyl)-2-methyl-1-(p methylsulfinylcinn-amylidenyl)-indene.

Similarly, when an equivalent amount of any one of the other1-(p-methylsulfinylcinnamylidenyl)-3-indenyl-/S- ethanol compoundsobtained from Example 2(B) are used in place of5-fluoro-2-methyl-1-(4'-methylsulfinylcinnamylidenyl)-3-indenyl ethanolin the above example,

there is obtained the corresponding 3-(methoxyethyl) compound.

Similarly, when an equivalent amount of any one of the1-substituted-2-methyl-5-fluoro-3-indenyl-5 ethanol compounds obtainedfrom Example 2(B) are used in place of the indenyl-B-alcohol above,there is obtained the correspondingly 1-substituted-3-(methoxyethyl)compound.

Similarly, when an equivalent amount of ethyl iodide, benzyl iodide oracetylchloride is used in place of methyl iodide in the above example,there is obtained the corresponding ethoxyethyl, benzyloxyethyl,acetoxyethyl compound.

EXAMPLE 4 (A) Methyl 5-fluoro-2-methyl-3-indenylformate A mixture of6-fluoro-2-methyl-l-indanone (49.2 g., 0.30 mole), activated zinc dust(25.4 g., 0.40 mole), ethyl chloroformate (32.6 g., 0.3 mole) and acrystal of iodine in dry benzene (1.5 liters) is refluxed for 5 hours.The mixture is poured into sulfuric acid (5%, 1.5 liters) and extractedwith ether, the ether extract dried (MgSO and the ethereal solutionconcentrated. The crude ester is redissolved in benzene (440 ml.),phosphorus pentoxide (88 g.) added and the resulting mixture refluxedfor 30 minutes. The mixture is decanted, the residue washed withbenzene, the benzene layers are combined, washed with water, saturatedsalt solution and dried (MgSO The benzene solution is concentrated invacuo and the residue recrystallized from ethyl acetate-n-hexane toobtain methyl 5-fluoro-2-methyl-indenylformate.

Similarly, when an equivalent amount of5,6-difluoro-2-methy1-l-indanone, 6-cyano-2-methyll-indanone,6-dimethylamino-2-methyl-l-indanone, 6-allyloxy-2-methyl- 1 -indanone,S-fluoro-6-methoxy-2-methyll-indanone, 6-methoxy-2-methyll-indanone,4-fluoro-2-methyl-l-indanone, or 6-trifluoromethyll-indanone is used inplace of 6-fluoro-2-methyl-l-indanone in the above example, there isobtained the corresponding methyl-3-indenylformate.

(B) 5-Fluoro-3-hydroxymethyl-2-methylindene "Methyl5-fluoro-2-methylindenylformate (41.2 g., 0.2 mole) by the method ofExample 2(A) is covered to the subject compound.

Similarly, the other methyl-3-indenylformate compounds are converted totheir 3-hydroxymethyl compounds.

(C) cisand trans-S-Fluoro-3-hydroxymethyl-2-methyl-1-(p-methylsulfinylcinnamylidenyl)-indene5-Fluoro-3-hydroxymethyl-2-methylindene (0.1 mole) by the method ofExample 2(B) is converted to the subject compound.

Similarly, the other 3-hydroxymethyl compounds from 4(B) above areconverted to their l-(p-methylsulfinylcinnamylidenyl) compounds.

Similarly, when an equivalent amount of the aldehydes as described inExample 2 are used in place of p-methylsulfinylcinnamaldehyde in Example4(C) above, there are obtained the corresponding 1-substituted-3-indenylmethanol compounds.

(D)cis'5-Fluoro-3-methoxymethyl-2-methyl-1-(p-methylsulfinylcinnamylidenyl)-indene cis-S-Fluoro-S-hydroxymethyl-2-methyl-1-(pmethylsulfinylcinnamylidenyl)-indene (0.01 mole) by the method ofExample 3 is converted to the subject compound.

Similarly, the other 1-(p-methylsulfinylcinnamylidenyl) compounds fromExample 4(C) above are converted to their methoxymethyl derivatives.

8 EXAMPLE 5 cisandtravzs-S-Fluoro-2-methyl-1-(p-methylthiocinnamylidenyl)-3-indenylethanol To a solution of 5-fluor0-2-methyl-3-indenyl ethanol (0.020mole) in methanol (60 ml.) is added sodium methoxide (2.16 g., 0.04mole) and after solution p-methylthiocinnamaldehyde (0.02 mole). Themixture is heated at reflux for 5 hours, cooled, poured intoether-water, extracted with ether, dried (MgSO and concentrated to anoil in vacuo. The oil is taken up in methylene chloride andchromatographed on silica gel and eluted with ethyl. acetate. Thefractions of eluate are concentrated to yield cisandtrans-5-fluoro-2-methyl-l-(p-methylthiocinnamylidenyl)-3-indenylethanol.

EXAMPLE 6 (A) 5 -Fluoro-2-methyl-3- 2'-methoxyethyl -indene To5-fluoro-2-methyl-3-indenyl ethanol from Example 2(A) (0.0017 mole) indimethoxyethane (10 ml.) is added oil-free sodium hydride (0.048 g.,0.002 mole) and the mixture is stirred at 25 for 1 hour. To the mixtureis added methyl iodide (2.28 g., 0.016 mole) and stirring at 25 iscontinued for 18 hours. The mixture is poured into methylenechloride-water, extracted with methylene chloride, the methylenechloride extract washed with Water, dried (MgSO and concentrated. Theconcentrate is chromatographed over silica gel and the eluateconcentrated to yield 5-fluoro-2-methyl-3-(2-methoxyethyl)- indene.

(B) cis-5-Fluoro-3- (2'-methoxyethy1) -1-(p-methylthiocinnamylidenyl)-indene A solution of Example 6 is condensedwith p-methylthiocinnamaldehyde using the procedure of Example 5 toyield the subject compound.

EXAMPLE 7 (A) (3-Chloro-4-methylthio)-phenylpropargaldehyde A mixture of3-chloro-4-methylthiocinnamaldehyde (2.0 mole) and acetic acid (1.5liter) is stirred vigorously while bromine (320 g., 2.0 mole) is addeddropwise at 25 Powdered anhydrous potassium carbonate is added at 25When the evoluation of gas stops the mixture is refluxed for 30 minutes,cooled and poured into cold water (2.5 liter). The mixture is cooled to0-5" with stirring and stirred at this temperature overnight. Theprecipitate is separated by filtration without drying and crystallizedfrom ethanol-water. 3-Chloro-4-methylthio-ubromocinnamaldehyde isfiltered, washed and dried in air.

The aldehyde 1.6 mole), methyl orthoformate (244 g., 2.3 mole), absoluteethanol (320 ml.) and ammonium chloride (4.0 g.) are refluxed for 30minutes, low boiling components distilled at atmospheric pressure anddistilled in vacuo to yieldl,1-dirnethoxy-3-(3'-chloro-4'-methylthiophenyl)-2-propene. To thiscompound (1.35 mole) is added potassium hydroxide (132 g., 2.0 moles) inmethanol (1400 ml.). The mixture is refluxed for 3 hours and poured intowater (11.3 liter). The mixture is extracted with chloroform (3 X 1.5liter), the combined chloroform extracts washed with water (3X 660 ml.)and dried (Na SO The chloroform is distilled and the residuefractionated in vacuo to obtain 1,l-dimethoxy-(3'-chloro-4-methylthiophenyl)-2-propane. This compound (1.0 mole) is added towater (1 liter) containing concentrated sulfuric acid (70 ml.) and themixture is heated on the steam bath for 30 minutes with occasionalmixing. The mixture is extracted with ether (3X 750 ml.), the etherextract washed with water and saturated salt solution, dried (NagSO) andconcentrated to an oil at atmospheric pressure. The oil is distilled invacuo to yield (3-chloro-4- methylthio)-phenyl propargaldehyde.

(B) cisand trans 5 Fluoro-Z-methyl-l-(3'-chloro-4-methylthiophenylpropargylidene) -34ndenyl-fl-ethanol(3-Chloro-4-methylthio)-phenylpropargaldehyde (0.2 mole) and ethyl-fluoro-2-methyl-3-indenyl- 3-ethanol (0.2 mole) are condensed by themethod of Example 2(B) to yield the subject compounds.

Using the same reaction conditions and techniques, the followingcompounds are obtained:

Starting material Product Ethyl 5,6-difiuoro-2-methylcisandtrans-5,6-difluoro-2-methyl-l- 3-indenyl-fl-ethanol.(3-chloro-4-methylthiophenylpropargylldene)-3-indenyl ethanol. Ethyl5-methoxy-6-fiuoro-2- ciaand trans-5-methoxy-6-flu0ro-2-methyl-B-lndenyl-fl-ethanol. methyl-1-(3-chloro-4-methylthiophenylpropargylidene)-3-indenyl ethanol.

Ethyl 5-dimethylamln0-2- cisand trans-5-dimethylarnlno-2-methyl-3-indenyl-fl-ethanol. methyl-l-(3-ehloro-4-rnethylthiophenylpropargylidene)-3- indenyl ethanol. Ethyl5-allyloxy-2-methylcisand trans-li-allyloxy-Z-methyl-l-3-lndenyl-fl-ethan0l.(3-chloro-4-methylthiophenylpropargylidene)-3-indenyl ethanol. Ethyl5-cyano-2-methyl-3- cisand trans-5-eyano-2-methyl-1- indenyl-fl-ethanol.(8-ehloro-4-methylthiophenylpropargylindene) -3-indeuyl ethanol. Ethyl6-flu0ro-2-methy1-3- cz'sand transfi-fiuoro-methyllindenyl-fi-ethanol.(3-chloro-4-methylthiophenylpropargylidene)-3-indenyl ethanol.

EXAMPLE 8 (A) t-Butyl 5-fluoro-2-methyl-3-indenyl-a-propionate Ethyl5-fluoro-2-methyl-3indenyl-propionate (246.3 g., 1.0 mole), t-butylacetate (700 g., 6.0 mole) and sodium methoxide (108 g., 2 mole) undernitrogen are stirred and refluxed at 10:1 ratio through a 1.5-columnpacked with glass A3" helices. The mixture is distilled for 18 hours and250 m1. of distillate is collected. The excess of t-butylacetate isdistilled in vacuo and the resi due is taken up in methylene chloride,filtered through diatomaceous earth then through acid-washed alumina.The methylene chloride is removed and the residue crystallized fromacetone-n-hexane to yield t-butyl 5-fluoro-2-methyl-3-indenyl-a-pr0pionate.

B) t-Butyl S-fluoro-1-hydroxymethylene-2-methyl-3- indenyl-a-propionate,sodium salt To a mixture of t-butyl5-fiuoro-2-methyl-3-indenyl-apropionate (55.3 g, 012 mole) in benzene(500 ml.) and ethyl formate (74.1 g., "1.0 mole) is added oil-freesodium hydride (7.2 g., 013 mole). The mixture is stirred at roomtemperature 1 hour each day for 2 days. Any remaining sodium hydride isdecomposed by the addition of methanol (20 ml.) in ether 100 ml.). Thesalt is filtered, washed with ether and dried in vacuo.

( C) cisandtrans-'5-Fluoro-2-methyl-1-(p-methylthiophenoxymethylidene)-3-t-butyl-indeny1-u-propionateThe sodium salt (32.6 g., 0.01 mole) from Example 8( B) indimethoxyethane (200 ml.) is heated at reflux with stirring for hourswith p-methylthiophenyl iodode (25.0 g., 0.01 mole). The mixture isconcentrated in vacuo to remove solvent, taken up in methylenechloridewater, the layers separated and the water layer extracted withmethylene chloride (2x 100 ml.). The combined 10 methylene chloridelayers are concentrated to /3 volume and chromatographed over silica geland eluted by methanolic chloroform to separate cisand trans-isomers.

0D) 5-Fluoro-2-methyl-1-(p-methylthiophenoxymethylidene)-3-indenyl-a-propanol The product ofStep (C) above is reacted in accordance with Example 2(A) to yield thesubject product.

Similarly, when an equivalent amount of p-methylsulfinylphenyliodide isused in place of p-methylthiophenyliodide in Example 8 (C) above and theproduct reacted by the method of 8(D) above, there is obtained thecorresponding 1 (p methylsulfinylphenoxymethylidene) compound.

Similarly, when an equivalent amount of any one of the ethyl acetatecompounds obtained from Example 1 is used in place oft-butyl-5-fiuoro-2-methyl 3 -indenyl-apropionate in Example 8 (B) aboveand the resulting product used in Example 8(C) followed by 8(D), thereis obtained the corresponding 1 (p methylthiophenoxymethylidene)3-indenyl-fl-ethanol compound.

EXAMPIJE 9 5-Fluoro-3-(2-methylethyl) 2-methy1-1-(p-methylthiophenoxymethylidene)-3-indene The method of Example 3 iscarried out using an equivalent amount of 5fiuoro-2-methyl-'l(pmethylthiophenoxymethylidene)-3-indenyl-l8-ethanol in place of S-fiuoro-'2-methyl-1-(p-methylsulfinylcinnamylidenyl)-3 indenylfl-ethanol, thesubject compound is obtained.

EXAMP'LE 10 (A) 5-Fluoro-3(2-methoxyethyl)-2-methyl indene 'Theprocedure of Example 3 is carried out using an equivalent amount of'5-fluoro-2-methyl 3 indenyl )3- ethanol in place of5-fiuoro-2-methyl-1-'(p-methylsulfinylcinnamylidenyl)-indenyl-,B-ethanol to obtain the subject compound.

(B) S-Fluoro-B (2-methoxyethyl) -2'methyl1-(p-methylsulfinylcinnamylidenyl) -indene The product of Example 10(A)above is used in place of (in an equivalent amount)5-fluoro-2-methyl-3-indenylfl-ethanol in Example 2(B), and saidprocedure carried out to yield the subject compound.

A mixture of 260 parts of5-fluoro-2-methyl-l-(p-methylsulfinylcinnamylidenyl)-3-.indenyl-B-ethanol and 25 parts of lactose is granulated withsuitable water and to this is added parts of maize starch. The mass ispassed through a 16 mesh screen. The granules are dried at a temperaturebelow 60 C. The dry granules are passed through a 16 mesh screen andmixed with 3.8 parts of magnesium stearate. They are then compressedinto tablets suitable for oral administration.

Similarly, when 250 parts of cis-S-fluoro-B-(Q-methoxyethyl)-2 methyl1-(p-methylsulfinylcinnamylidenyl) -indene,

cisandtrans-S-fluoro-Z-methyl-l-(3-chloro-4'-methylthiophenylpropargylidene)-3-indenyl-fl-ethanol,

5-fluoro-'2-methyl-'1-( p-methylthiophenoxymethylidene)-3-indenyl-a-propan0l,

'5 -fiuoro-3- 2-methoxyethyl) -2-methyl- 1-(p-methylthiophenoxymethylidene -3 -indene,

5-fluoro 2-methyl-1-(p-methylsulfinylphenoxymethylidene)-3-indenyl-a-propanol, or

5-fluoro-2-methyl1-(p-methylsulfinylphenoxymethylidene)-3-indenyl-p-ethanol is used inplace of 5-fluoro-2-methyl-l-methylsulfinylcinnamyl1denyl-3-indenyl ,8ethanol in the above example, tablets suitable for oral administrationare obtained.

-11 What is claimed is: 1. A compound of the formula:

, gm R Y-m l i go R3 R wherein:

n is 1 or 2;

@ is phenyl; and

M is hydrogen, C loweralkyl, phenyl or benzyl.

2. The compound of claim 1 wherein R and R is hydrogen, C loweralkyl,phenyl or benzyl; R is hydrogen or C loweralkyl; R R R and R are eachhydrogen, chloro, bromo, fluoro, C loweralkyl, C loweralkoxy, nitro,amino, halo C loweralkyl, C loweralkanoyloxy, hydroxy ortrifluoromethyl, at most only 2 of R R R or R, being other than hydrogenat any one time; R and R are each hydrogen, C loweralkyl, C loweralkoxy,C loweralkylsulfinyl, C loweralkylsulfonyl, chloro, bromo, fluoro, Cloweralkylthio, trifluoromethyl, C diloweralkylsulfamyl or nitro; X is Calkylene, C alkenylene, C alkynylene or O-; n is 1 or 2; and M ishydrogen, C loweralkyl, benzyl or phenyl.

3. The compound of claim 2 wherein X is C alkylene, C alkenylene, Calkynylene or O.

4. The compound of claim 2 wherein:

R is hydrogen;

R and R are each hydrogen or loweralkyl;

R to R are each hydrogen, chloro, bromo, fluoro,

C loweralkyl, C loweralkoxy or C loweralkenyloxy;

R and R are each hydrogen, chloro, bromo, fluoro C loweralkoxy, Cloweralkylsulfinyl, C loweralkylthio or C loweralkylsulfonyl;

M is hydrogen or C loweralkyl;

n is 2; and

X is C alkylene, C alkynylene or O.

5. The compound of claim 4 wherein:

R is hydrogen;

R is methyl;

R R R and R are each hydrogen;

R is methylsulfinyl, or methylsulfonyl or methylthio;

and

M is hydrogen.

6. The compound of claim 5 wherein R is methylsulfinyl.

References Cited UNITED STATES PATENTS 5/ 1973 Hinkley et al 260-607 A2/1972 Shen et a1. 260-618 F U.S. Cl. X.R.

260618 F, 465 R, 466 L, 609 F, 611 A, 558 S, 558 A, 596 R, 508; 424-337,339, 343

zg gg UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,819,716 Dated June 25. A1974 lnventr(s)ard Jones It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

In Claim 1, line 29, "C alkylene should read "C 4 alkylene.

Signed and sealed this 29th day of October 1974.

(SEAL) Attest:

McCOY M. GIBSON JR. c'. MARSHALL DANN Commissioner of Patents AttestingOfficer

